CHICAGO -- The investigational PCSK9 drug alirocumab lowered lipids substantially more for statin-intolerant patients than did ezetimibe (Zetia), a trial showed, although questions were raised over dropout and approvability.

For patients unable to tolerate two or more prior statins even at the lowest dose, the monoclonal antibody cut LDL by an average 45.0% compared with 14.6% on 10-mg, once-daily ezetimibe at 6 months (84 versus 33 mg/dL, P<0.0001), Patrick Moriarty, MD, of the University of Kansas Medical Center in Kansas City, and colleagues found.

Alirocumab also reduced skeletal-muscle adverse events compared with 20-mg, once-daily atorvastatin (Lipitor) as the third arm of the double-blind portion of the trial (32.5% versus 46.0%), they reported here at the American Heart Association meeting.

Adverse events overall were 63% more likely with the statin than the PCSK9 drug (75 mg self-injection every 2 weeks, up-titrated to 150 mg for half), suggesting better tolerability in this notoriously difficult-to-treat patient population.

But those adverse events and related discontinuation rates highlighted some serious concerns for interpretation of the results, cautioned Noel Bairey Merz, MD, director of the Preventive and Rehabilitative Cardiac Center at the Cedars-Sinai's Heart Institute in Los Angeles.

Of the 314 patients who could be randomized without reporting muscle-related events during a 4-week, double-blind placebo phase, 23.8% dropped out on alirocumab, 33.6% on ezetimibe, and 33.3% on atorvastatin.

The vast majority were due to adverse events reported on treatment.

"This very high dropout rate in all of the blinded arms tells me that these side effects likely are psychosomatic," Merz told MedPage Today. "We certainly didn't see these high types of high adverse events -- myalgias -- with ezetimibe previously.

"I think this tells us that these patients likely have other disorders, perhaps anxiety disorders or psychosomatic disorders that we are not going to be able to address with lipid-lowering therapy."

"But there are truly patients who are statin intolerant," argued study discussant Karol Watson, MD, PhD, co-director of the UCLA Program in Preventive Cardiology.

One in four of her referral lipid clinic patients fit that bill, she said. "I don't think it's psychosomatic at all."

But in support of the psychosomatic explanation was the fact that adverse event-related discontinuations dropped to just 2.8% once patients knew they were getting alirocumab in an open-label phase afterward, Merz suggested.

She questioned, too, whether the FDA would accept a trial with dropout rates well above the 20% threshold often considered to indicate a low-quality trial. A marketing application has not yet been filed for alirocumab with the FDA.

For this tough patient population, "you're always going to get about that amount of dropout," Watson pointed out in an interview, calling the trial reasonable.

While enthusiastic about a potential new class of drug for this patient population, she agreed that the FDA was unlikely to approve alirocumab for statin intolerance, in part because the drugs were fast-tracked for familial hypertension as an orphan disease, whereas statin intolerant individuals are much lower risk and would need long-term safety data.

"We've been burned too many times on other lipid therapies," Watson told MedPage Today.

Another concern is the lack of an accepted, standard definition of statin intolerance.

Moriarty's ODYSSEY Alternative trial defined it as unable to tolerate at least two different statins, including one at the lowest dose, due to muscle-related symptoms.

The National Lipid Association has been the only organization to attempt a definition, Moriarty noted.

"You sometimes might have a physical diagnosis of elevated CPK [creatine phosphokinase] enzymes so you can correlate that, but not every myalgia is associated with elevated muscle enzymes. It's difficult to diagnose," he told MedPage Today at a press conference. "They are very, very complex, difficult, significant in number population of patients we see every single day."

That group defines statin intolerance as "adverse symptoms, signs, or laboratory abnormalities attributed by the patient (or provider) to the statin and in most cases perceived by the patient to interfere unacceptably with activities of daily living (such as sleep, work/housework, or leisure-time activity), leading to a decision to stop or reduce statin therapy."

While ezetimibe is a common lipid-lowering approach for statin-intolerant patients, it was promising that so many of these patients labeled statin-intolerant were actually able to tolerate a statin when given it in a blinded manner in the trial, Watson noted.

She suggested that her clinical strategy, armed with this data, would be to attempt a statin first -- even if a PCSK9 drug were approved.

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